The broad objective of this program is to develop new basic information on conformational and other structural changes in the globular proteins. Experimental studies, primarily biophysical in character, are being conducted on certain model proteins, primarily plasma albumin. Past emphasis on reversible cooperative changes in conformation has led to the demonstration of several such transitions in both human and bovine plasma albumins. One such transition now appears to occur under physiological conditions and probably is allosteric in the sense that it is sensitive to both pH and Ca ions concentration. This transition will be studied further with particular attention to its possible role in the control of Ca ion activity in the bloodstream and transport of lipids. Previous studies have also demonstrated that these proteins are microheterogeneous, consisting of populations of molecules which differ in their conformational stability. It now appears that the structural differences responsible for such microheterogeneity are at least in part covalent and may result from modifications of the protein during its limited life time. A major objective of the program in the future is the exploration of this possible explanation for the in vivo turn-over of albumin as well as elucidation of the possible enzymatic mechanism for removing damaged molecules from the circulatory system. Thus, an immediate objective is the more detailed study of the influence of substrate protein conformation on its susceptibility to proteolysis.